Effect of dietary cholesterol on low density lipoprotein‐receptor, 3‐hydroxy‐3‐methylglutaryl‐CoA reductase, and low density lipoprotein receptor‐related protein mRNA expression in healthy humans

Abstract

We investigated the possibility that dietary cholesterol downregulates the expression of low density lipoprotein (LDL) receptor and 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase genes of circulating mononuclear cells in vivo in healthy humans. We also studied the variations of the LDL receptor-related protein (LRP) gene in the same conditions. Dieters (n = 5) were submitted to a 4-d fat restriction (mean cholesterol intake: 6+/-4 mg/d), followed by a 7-d cholesterol (a mean of 791+/-150 mg/d) supplementation. Controls (n = 3) did not change their diet. During fat restriction, serum total and LDL cholesterol decreased significantly (P < 0.05), and LDL receptor and HMG-CoA reductase mRNA copy numbers in mononuclear cells increased by 57 and 147%, respectively (P < 0.05). After reintroducing cholesterol, serum cholesterol was stable whereas LDL receptor and HMG-CoA reductase mRNA decreased by 46 and 72% (P < 0.05) and LRP mRNA increased by 59% (P < 0.005). The changes in LDL receptor and HMG-CoA reductase mRNA abundance were correlated (r = +0.79, P = 0.02) during cholesterol reintroduction as were LDL receptor and LRP mRNA levels, but negatively (r = -0.70, P = 0.05). Also, 70% of the variability in LRP mRNA (P < 0.005) was explained by dietary cholesterol. Thus, the basic mechanisms regulating cellular cholesterol content, the coordinate feedback repression of genes governing the synthesis and uptake of cholesterol, are operating in vivo in humans. However, serum cholesterol did not increase in response to dietary cholesterol, suggesting that these mechanisms may not play as predominant a role as previously believed in the short-term control of serum cholesterol in vivo in humans. A new finding is that LRP gene is also sensitive to dietary cholesterol, suggesting that it may participate in the control of serum cholesterol. Further in vivo studies in humans are warranted to explore the molecular mechanisms of the physiological response to dietary cholesterol in humans.

Low-Density Lipoprotein Upregulates Low-Density Lipoprotein Receptor-Related Protein Expression in Vascular Smooth Muscle Cells

“…LRP upregulation in hypercholesterolemic aortas is concomitant with the SREBP-2 downregulation previously described by our group. 31 Our results in vivo are in agreement with those obtained in blood mononuclear cells, in which dietary cholesterol has been shown to increase LRP mRNA levels, 32 and in aortas of Watanabe rabbits, although the main cellular component at both early and late stages of atherosclerosis in this animal model are infiltrated macrophages. 33 To our knowledge, this is the first demonstration that exposure to high LDL concentration and cellular accumulation of CE increases LRP expression in VSMCs.…”

LDL Receptor–Related Protein and the Vascular Wall

“…38 Our results in vivo are also in agreement with those obtained in blood mononuclear cells, in which dietary cholesterol has been shown to increase LRP1 mRNA levels. 39 Therefore, exposure to high LDL concentrations and cellular accumulation of CEs increase LRP1 expression in VSMCs. 31 Our results suggest that hypercholesterolemia might increase the capacity of VSMCs to take up LDL from the intima by regulating cellular LRP1 levels.…”

Mechanisms of the Triglyceride- and Cholesterol-Lowering Effect of Fenofibrate in Hyperlipidemic Type 2 Diabetic Patients

“…Mononuclear cells were immediately isolated by centrifugation of whole venous blood on a Ficoll gradient at 4°C as described (25) and stored at Ϫ80°C. Total RNA was prepared from frozen samples as described previously (26). Total RNA was then quantified by electrophoresis on 1% agarose gel of serial dilutions compared with known amounts of standard RNA (Boehringer Mannheim).…”